Glial cell line-derived neurotrophic factor (GDNF) was initially identified for its ability to promote survival of midbrain dopamine neurons (Lin et al., Science 260:1130-1132, 1993) and its neurotrophic actions have been extensively studied in animal models of Parkinson's disease (Chiocco et al., Parkinsonism Relat Disord 13 Suppl 3:S321-328, 2007). However, its actions are not specific for dopamine neurons; GDNF regulates neurite branching, synaptic plasticity, and phenotypes of several neuronal populations (Airaksinen and Saarma, Nat Rev Neurosci 3:383-394, 2002). Exogenous GDNF supports survival of noradrenergic neurons (Arenas et al., Neuron 15:1465-1473, 1995), spinal motor neurons (Henderson et al., Science 266:1062-1064, 1994; Trok et al., Neuroscience 71:231-241, 1996), peripheral sensory and autonomic neurons (Trupp et al., J Cell Biol 130:137-148, 1995), forebrain cholinergic and GABAergic neurons (Williams et al., J Pharmacol Exp Ther 277:1140-1151, 1996) and pancreatic β-cells (Mwangi et al., Gastroenterology 134:727-737, 2008). Furthermore, GDNF protects the brain from ischemic injury (Wang et al., J Neurosci 17:4341-4348, 1997) and ameliorates neuropathic pain (Boucher et al., Science 290:124-127, 2000). In peripheral tissues, GDNF promotes differentiation of kidney, lung, pancreas, germ cells, myocytes, and thymocytes, and influences gastrointestinal inflammation and tumorigenesis (Farhi et al., Fertil Steril 93:2565-2571, 2010; Kondo et al., Eur J Immunol 33:2233-2240, 2003; Little et al., Curr Top Dev Biol 90:193-229, 2010; Martinelli et al., Histochem Cell Biol 118:337-343, 2002; von Boyen et al., BMC Gastroenterol 11:3, 2011; Watanabe et al., Gastroenterology 136:2149-2158, 2009; Fromont-Hankard et al., Arch Pathol Lab Med 126:432-436, 2002; Lucini et al., Eur J Histochem 52:69-74, 2008).
GDNF is synthesized in a precursor form, pre-pro-GDNF, that is processed into the mature form, packaged into vesicles and released upon neuronal activity (Lin et al., Science 260:1130-1132, 1993). Previous studies have shown that the human and rodent GDNF genes have three exons encoding two mRNAs that are produced by alternative splicing of exon 2: pre-(α)long-pro-GDNF and pre-(β)short-pro-GDNF, with the (β)short isoform lacking 26 amino acids in the pro-region (Trupp et al., J Cell Biol 130:137-148, 1995; Grimm et al., Hum Mol Genet. 7:1873-1886, 1998; Matsushita et al., Gene 203:149-157, 1997; Matsushita et al., Gene 203:149-157, 1997). Recent studies have indicated that both forms are secreted from neurons, but secretion of the (β)short-pro-GDNF and the corresponding mature GDNF is activity-dependent, whereas (α) long-pro-GDNF and its mature GDNF are secreted constitutively in an adrenal gland pheochromocytoma PC-6.3 cell line (Lonka-Nevalaita et al., J Neurosci 30:11403-11413, 2010). Site-directed mutagenesis has shown that the pro-region and C-terminal cysteines are important for GDNF processing and secretion (Oh-hashi et al., Mol Cell Biochem 323:1-7, 2009). Pre-pro-GDNF processing and secretion are not well studied with respect to the different isoforms, especially in humans where isoforms are more heterogeneous in pre-pro-regions than in those of the rodent.
GDNF is known to be down-regulated in substantia nigra and putamen in human Parkinson's disease (Backman et al., Mol Cell Endocrinol 252:160-166, 2006; Chauhan et al., J Chem Neuroanat 21:277-288, 2001; Hunot et al., J Neural Transm 103:1043-1052, 1996); however GDNF regulation in Alzheimer's disease (AD) is less documented (Siegel and Chauhan, Brain Res Brain Res Rev 33:199-227, 2000). A prior study indicated that GDNF concentrations are significantly up-regulated in cerebrospinal fluid and down-regulated in serum in patients with early AD (Straten et al., J Alzheimers Dis 18:331-337, 2009).